In recent years therapeutic medicine has become increasingly concerned with the physiological role of nitric oxide, NO. "Overproduction" of NO has been implicated in pathological conditions such as sepsis and cellular toxicity observed in dopanergic neurons with Parkinson's disease. In vivo, nitric oxide is formed by nitric oxide synthase. A number of nitric oxide synthase modulators have been identified, with particular reference to nitric oxide synthase inhibitors.
This invention is particularly concerned with nitric oxide synthase activity modification with particular reference to 2,4-diamino-5,6,7,8-tetrahydro-6-(L-erythro-1,2-dihydroxylpropyl)pteridine (both as to the 6R form and the 6S form), also termed tetrahydroaminobiopterin, a nitric oxide synthase inhibitor as represented in Table I (I). Attention is drawn to 2,4-diamino-5,6,7,8-tetrahydro-6-hydroxymethyl pteridine, a nitric oxide synthase inhibitor as represented in Table I (III). See, DE 44 18 097.
In one embodiment, this invention is concerned the nitric oxide synthase inhibitor, 2,4-diamino-7,8-dihydro-6-(L-erythro-1,2-dihydroxylpropyl)pteridine, also termed 7,8 dihydroaminobiopterin, or H.sub.2 aminobiopterin, as represented in Table I (IV).
Other nitric oxide synthase inhibitors are L-NMMA, L-NAME, NG, NG-dimethyl-L-arginine, L-NMEA (NG-monoethyl-L-arginine), L-NIO (N-imino-ornithine, L-iminoethyl-lysine, L-thiocitrulline, aminoguanadine, iminobiotin L-amino arginine, 7-nitroindazol, NG-methylarginine, and NG-nitroarginine. Attention is also drawn to pteridines as disclosed in DE 44 18 096, and the tetrahydropteradines of DE 44 18 097.
Without being bound by any particular theory or mechanism of action, it is noted that nitric oxide synthase tightly binds the 5,6,7,8,-tetrahydro-L-erythro-biopterin
TABLE I ______________________________________ ##STR3## 1 tetrahydroamino- biopterin (I) 2 #STR4## aminobiopterin (II) 3 #STR5## 2,4,-diamino- 5,6,7,8-tetra hydro-6- hydroxymethyl pteridine (III) 4 #STR6## 2,4,-diamino- 7,8-dihydro- 6-(L-erythro- 1,2,dihydroxy propyl)pteridine (IV) ______________________________________
moiety ("tetrahydrobiopterin"). And further that, in vivo, availability of tetrahydrobiopterin appears to be a rate limiting step. Thus, the addition of exogenous tetrahydrobiopterin is required for nitric oxide synthase to reach full activity. This invention is drawn to substances and methods which exploit this finding.